tbuckley/cabot-search huggingface dataset:
A TEMPOL and rapamycin loaded nanofiber-covered stent favors endothelialization and mitigates neointimal hyperplasia and local inflammation
Authors: Rui Wang, Jian Lu, Jiasheng Yin, Han Chen, Hongmei Liu, Fei Xu, Tongtong Zang, Rende Xu, Chenguang Li, Yizhe Wu, Qilin Wu, Xiang Fei, Meifang Zhu, Li Shen, Junbo Ge
Journal: Bioactive Materials (2022)

An increased level of reactive oxygen species (ROS) plays a major role in endothelial dysfunction and vascular smooth muscle cell (VSMC) proliferation during in-stent thrombosis and restenosis after coronary artery stenting. Herein, we report an electrospun core-shell nanofiber coloaded with 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL) and rapamycin (RAPA) that correspondingly serves as an ROS scavenger and VSMC inhibitor. This system has the potential to improve the biocompatibility of current drug-eluting stent (DES) coatings with the long-term and continuous release of TEMPOL and rapamycin. Moreover, the RAPA/TEMPOL-loaded membrane selectively inhibited the proliferation of VSMCs while sparing endothelial cells (ECs). This membrane demonstrated superior ROS-scavenging, anti-inflammatory and antithrombogenic effects in ECs. In addition, the membrane could maintain the contractile phenotype and mitigate platelet-derived growth factor BB (PDGF-BB)-induced proliferation of VSMCs. In vivo results further revealed that the RAPA/TEMPOL-loaded covered stents promoted rapid restoration of vascular endothelium compared with DES and persistently impeded inflammation and neointimal hyperplasia in porcine models.
Protective mechanisms and current clinical evidence of hypothermic oxygenated machine perfusion (HOPE) in preventing post-transplant cholangiopathy
Authors: Andrea Schlegel, Robert J. Porte, Philipp Dutkowski
Journal: Journal of Hepatology (2022)

The development of cholangiopathies after liver transplantation impacts on the quality and duration of graft and patient survival, contributing to higher costs as numerous interventions are required to treat strictures and infections at the biliary tree. Prolonged donor warm ischaemia time in combination with additional cold storage are key risk factors for the development of biliary strictures. Based on this, the clinical implementation of dynamic preservation strategies is a current hot topic in the field of donation after circulatory death (DCD) liver transplantation. Despite various retrospective studies reporting promising results, also regarding biliary complications, there are only a few randomised-controlled trials on machine perfusion. Recently, the group from Groningen has published the first randomised-controlled trial on hypothermic oxygenated perfusion (HOPE), demonstrating a significant reduction of symptomatic ischaemic cholangiopathies with the use of a short period of HOPE before DCD liver implantation. The most likely mechanism for this important effect, also shown in several experimental studies, is based on mitochondrial reprogramming under hypothermic aerobic conditions, e.g. exposure to oxygen in the cold, with a controlled and slow metabolism of ischaemically accumulated succinate and simultaneous ATP replenishment. This unique feature prevents mitochondrial oxidative injury and further downstream tissue inflammation. HOPE treatment therefore supports livers by protecting them from ischaemia-reperfusion injury (IRI), and thereby also prevents the development of post-transplant biliary injury. With reduced IRI-associated inflammation, recipients are also protected from activation of the innate immune system, with less acute rejections seen after HOPE.
Emerging NK cell therapies for cancer and the promise of next generation engineering of iPSC-derived NK cells
Authors: Sainiteesh Maddineni, John L Silberstein, John B Sunwoo
Journal: Journal for ImmunoTherapy of Cancer (2022)

Adoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor microenvironment. Expanded autologous T cells, particularly T cells with engineered T cell receptors (TCR) and chimeric antigen receptor-T cells have had success in various hematologic malignancies but have faced challenges when applied to solid tumors. As a result, other immune subpopulations may provide valuable and orthogonal options for treatment. Natural killer (NK) cells offer the possibility of significant tumor clearance and recruitment of additional immune subpopulations without the need for prior antigen presentation like in T or B cells that could require removal of endogenous antigen specificity mediated via the T cell receptor (TCR and/or the B ecll receptor (BCR). In recent years, NK cells have been demonstrated to be increasingly important players in the immune response against cancer. Here, we review multiple avenues for allogeneic NK cell therapy, including derivation of NK cells from peripheral blood or umbilical cord blood, the NK-92 immortalized cell line, and induced pluripotent stem cells (iPSCs). We also describe the potential of engineering iPSC-derived NK cells and the utility of this platform. Finally, we consider the benefits and drawbacks of each approach and discuss recent developments in the manufacturing and genetic or metabolic engineering of NK cells to have robust and prolonged antitumor responses in preclinical and clinical settings.
Regarding &amp;quot;Postresection Period-Specific Hazard of Recurrence as a Framework for Surveillance Strategy in Patients with Hepatocellular Carcinoma: A Multicenter Outcome Study&amp;quot;
Authors: Hiroshi Imamura, Kiyoshi Hasegawa, Yuji Soejima, Akio Saiura
Journal: Liver Cancer (2022)

We added a comment to the the article by Kim et al.. We first described how the hazard function and commonly used survival function act complementary, although these two functions are mathematically equivalent. Then, we pointed out two notable findings of the present article: 1) a recurrence by metastasis is presumed to occurred constantly at an annualized incidence of 4%-10% until 6 postoperative years; and 2) the annualized recurrence rates between the 5th and 10th postoperative years were between 3%-10% in cirrhotic patients and this figure was comparable to or even lower than the reported annual incidence of HCC in cirrhotic patients (up to 8%). We also pointed out three issues to be paid attention for: 1) the authors amalgamated patients with HBV- and HCV-related HCC together when calculating the hazard function, although the background liver of HCV-related HCC is hypothesized to have a higher carcinogenetic activity than that of HBV-related HCC, at least during the era before the advent of direct-acting antivirals; 2) the authors would have obtained interesting results had they evaluated the risk factors for late-phase recurrence exclusively in patients with HBV infection, including HBV-specific covariates into the analysis; and 3) many investigators may confuse a pathogenic factor with its surrogate marker when interpreting the significance of fibrosis in studies investigating risk factors leading to HCC development.
The clinical utility of dynamic ctDNA monitoring in inoperable localized NSCLC patients
Authors: Yin Yang, Tao Zhang, Jingbo Wang, Jianyang Wang, Yang Xu, Xiaotian Zhao, Qiuxiang Ou, Yang Shao, Xin Wang, Yuqi Wu, Linfang Wu, Xin Xu, Kunpeng Xu, Jingjing Zhao, Luhua Wang, Nan Bi
Journal: Molecular Cancer (2022)
The only thing that can stop bad causal inference is good causal inference
Authors: Julia M. Rohrer, Stefan C. Schmukle, Richard McElreath
Journal: Behavioral and Brain Sciences (2022)

Abstract In psychology, causal inference – both the transport from lab estimates to the real world and estimation on the basis of observational data – is often pursued in a casual manner. Underlying assumptions remain unarticulated; potential pitfalls are compiled in post-hoc lists of flaws. The field should move on to coherent frameworks of causal inference and generalizability that have been developed elsewhere.
Immune responses to COVID-19 vaccine BNT162b2 in workers at a research institute in Japan: 6-month follow-up survey
Authors: Akihiko Nishikimi, Ken Watanabe, Atsushi Watanabe, Mikako Yasuoka, Ryota Watanabe, Mitsuhiro Fujiwara, Hironori Oshima, Takeshi Nakagawa, Yuichi Kitagawa, Haruhiko Tokuda, Yukihiko Washimi, Shumpei Niida, Masayo Kojima
Journal: Journal of Infection (2022)
Abstract 235: Emergent PCI Is Associated with Good Neurological Outcome After OHCA
Authors: Hyun Wook Ryoo, Vatsal Chikani, Margaret Mullins, Tyler Vadeboncoeur, Taro Irisawa, Daniel Spaite, Bentley Bobrow
Journal: Circulation (2014)

Background: Previous observational studies have demonstrated that outcomes after OHCA can be significantly improved with therapies such as mild therapeutic hypothermia and percutaneous coronary intervention (PCI). However, the optimal candidate and timing for PCI in OHCA remains unknown. This study aimed to assess the impact of emergent PCI on survival and neurological outcome after OHCA. Methods: This is a prospective observational study from a statewide OHCA database in Arizona. Patients included were greater than 18 years old who received CPR and were admitted to one of 34 recognized cardiac receiving centers. Patients who did not achieve ROSC, died within 2 hours of hospital arrival, and DNAR patients were excluded since the likelihood of PCI impacting outcome in these patients is questionable. An in-hospital post-arrest database, including PCI (Y/N), was linked with an Utstein-style OHCA database. Univariate and multivariate logistic regression were utilized to assess the association between PCI and survival to hospital discharge and neurological outcome. Results: During this study period (1-1-2011-12-31-2013), there were a total of 6,543 adult OHCA patients. After exclusions, 782 patients with suspected cardiac etiology OHCA were analyzed. The median age of patients was 64.0 years (Q1:54.0, Q3:73.0) and 70.2% were male. Among them 458 (58.6%) and 238 (30.4%) patients underwent the emergency coronary angiogram (CAG), and Primary PCI, respectively. Among PCI patients, the rate of survival to hospital discharge was 75.2%, vs. 60.4% for those without PCI (p&lt;0.001) and good cerebral outcome (CPC 1-2) was found in 67.6%, vs. 44.3% of those without PCI (p&lt;0.001). After adjusting for age, gender, initial rhythm, bystander CPR, and hypothermia, the Odds Ratio was 1.2 (95% CI:0.8-1.8) for survival and 2.8 (95% CI:1.5-5.1) for good neurologic outcome (CPC 1-2) among PCI patients. Conclusion: This study shows an association with emergent PCI and good neurologic outcome after OHCA. Further study is necessary to determine a potential causal relationship between PCI and outcome.
Abstract 14422: Sarcomere Gene and Protein Expression Studies Suggest Mutation-Specific Disease Mechanisms in Human Hypertrophic Cardiomyopathy
Authors: David Coleman, Frank Davis, Francis Pagani, Jaime Predmore, Sarah Bartolone, Sakthivel Sadayappan, Ellen Pedersen, Robert Lyons, Richard Jones, Mark Russell, Sharlene M Day
Journal: Circulation (2011)

Heterozygous mutations in sarcomere genes cause hypertrophic cardiomyopathy (HCM), although the mechanisms by which these mutant proteins exert their effects in human disease are largely unknown. W...
Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research
Authors: Stephanie L. Bourke, Anne Katrin Schlag, Saoirse Elizabeth O'Sullivan, David J. Nutt, David P. Finn
Journal: Pharmacology & Therapeutics (2022)

Characterised by chronic widespread musculoskeletal pain, generalised hyperalgesia, and psychological distress, fibromyalgia (FM) is a significant unmet clinical need. The endogenous cannabinoid system plays an important role in modulating both pain and the stress response. Here, we appraise the evidence, from preclinical and clinical studies, for a role of the endocannabinoid system in FM and the therapeutic potential of targeting the endocannabinoid system. While many animal models have been used to study FM, the reserpine-induced myalgia model has emerged as perhaps the most translatable to the clinical phenotype. Inhibition of fatty acid amide hydrolase (FAAH) has shown promise in preclinical studies, ameliorating pain- and anxiety-related behaviour . Clinically, there is evidence for alterations in the endocannabinoid system in patients with FM, including single nucleotide polymorphisms and increased levels of circulating endocannabinoids and related N-acylethanolamines. Single entity cannabinoids, cannabis, and cannabis-based medicines in patients with FM show promise therapeutically but limitations in methodology and lack of longitudinal studies to assess efficacy and tolerability preclude the current recommendation for their use in patients with FM. Gaps in the literature that warrant further investigation are discussed, particularly the need for further development of animal models with high validity for the multifaceted nature of FM, balanced studies to eliminate sex-bias in preclinical research, and ultimately, better translation between preclinical and clinical research.
Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID‐19 in patients with chronic liver disease
Authors: Lukas Hartl, Katharina Haslinger, Martin Angerer, Georg Semmler, Mathias Schneeweiss‐Gleixner, Mathias Jachs, Benedikt Simbrunner, David Josef Maria Bauer, Ernst Eigenbauer, Robert Strassl, Monika Breuer, Oliver Kimberger, Daniel Laxar, Katharina Lampichler, Emina Halilbasic, Albert Friedrich Stättermayer, Ahmed Ba‐Ssalamah, Mattias Mandorfer, Bernhard Scheiner, Thomas Reiberger, Michael Trauner
Journal: Hepatology (2022)

Abstract Background and Aims Cholestasis is associated with disease severity and worse outcome in COVID‐19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection have been described. Approach and Results Hospitalized patients with COVID‐19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non‐advanced CLD (non‐ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non–COVID‐19 pneumonia were matched to patients with CLD and COVID‐19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS‐CoV‐2 infection (T1–T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% ( n = 65) had CLD (non‐ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID‐19–related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS‐CoV‐2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p &lt; 0.001) and gamma‐glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD ( n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID‐19, and 15.4% of patients ( n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID‐19 than in patients with CLD and non–COVID‐19 pneumonia ( p = 0.040). COVID‐19–associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% ( n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS‐CoV‐2 infection. Conclusions About 20% of patients with CLD develop progressive cholestasis after SARS‐CoV‐2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID‐19.
Programmed cell death-1/programmed death-ligand 1 expression and its association with mortality among patients with sepsis and hospital-acquired infections: Sepsimmune study
Authors: Dr. Praveen Tirlangi, Mr. Prabin Kumar, Dr. Mitra DK, Dr. Manish Soneja, Dr. Pandey RM, Dr. Sujay Halkur, Dr. Rachana Bhat, Dr. Sudheer Vuyyuru, Dr. Arti Kapil, Dr. Naveet Wig
Journal: Journal of Infection (2022)
Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection
Authors: Cecilie Egholm, Alaz Özcan, Daniel Breu, Onur Boyman
Journal: Science Immunology (2022)

Atopic individuals show enhanced type 2 immune cell responses and a susceptibility to infections with certain bacteria and viruses. Although patients with allergic diseases harbor normal counts of circulating neutrophils, these cells exert deficient effector functions. However, the underlying mechanism of this dysregulation of neutrophils remains ill defined. Here, we find that development, aging, and elimination of neutrophils are accelerated in mice with a predisposition to type 2 immunity, which, in turn, causes susceptibility to infection with several bacteria. Neutrophil-mediated immunity to bacterial infection was greatly decreased in mice with a genetic or induced bias to type 2 immunity. Abrogation of interleukin-4 (IL-4) receptor signaling in these animals fully restored their antibacterial defense, which largely depended on Ly6G + neutrophils. IL-4 signals accelerated the maturation of neutrophils in the bone marrow and caused their rapid release to the circulation and periphery. IL-4–stimulated neutrophils aged more rapidly in the periphery, as evidenced by their phenotypic and functional changes, including their decreased phagocytosis of bacterial particles. Moreover, neutrophils from type 2 immune predisposed mice were eliminated at a higher rate by apoptosis and phagocytosis by macrophages and dendritic cells. Collectively, IL-4 signaling–mediated neutrophil aging constitutes an important adaptive deficiency in type 2 inflammation, contributing to recurrent bacterial infections.
Cumulative corticosteroid-sparing effect of anti-interleukin-5/5Ra in eosinophilic asthma
Authors: Johannes A. Kroes, Sybrand W.J. Zielhuis, Kim De Jong, Simone Hashimoto, Jacob K. Sont, Sander W. Zielhuis, Eric N. Van Roon, Elisabeth H. Bel, Anneke Ten Brinke
Journal: European Respiratory Journal (2022)

Background Anti-interleukin (IL)-5/IL-5 receptor α (IL-5Ra) therapy has been shown to reduce maintenance oral corticosteroid (OCS) dose in severe eosinophilic asthma. However, the effect on cumulative OCS exposure is currently unknown. Neither is it known how prior OCS exposure affects response to anti-IL-5/5Ra treatment. We aimed primarily to compare the cumulative OCS exposure over a 2-year period before and after anti-IL-5/5Ra initiation, and secondarily to investigate whether duration and cumulative OCS exposure prior to anti-IL-5/5Ra influence the ability to discontinue OCS within 2 years of anti-IL-5/5Ra therapy. Methods This real-world nationwide observational registry-based study evaluated all dispensed OCS from 389 adults with severe eosinophilic asthma included in the Dutch Severe Asthma Registry (RAPSODI) 2 years before and 2 years after initiating anti-IL-5/5Ra. The Wilcoxon signed-rank test and multivariable regression analyses were used. Results Median (interquartile range) cumulative OCS exposure in the 2 years before and after anti-IL-5/5Ra initiation decreased from 2.715 (1.150–5.539) to 1.050 (0.300–3.640) g (p&lt;0.001). 52% of patients were able to discontinue OCS within 2 years after anti-IL-5/5Ra therapy, which was independently predicted by lower and shorter prior OCS exposure. Conclusions This real-world study showed that anti-IL-5/5Ra therapy leads to a significant reduction in cumulative OCS exposure over a 2-year period. Patients with lower and shorter OCS exposure were more likely to completely eliminate OCS. Since cumulative exposure increased progressively prior to anti-IL-5/5Ra initiation, our data suggest that early intervention leads to a better long-term prognosis in patients with severe eosinophilic asthma.
Genetic overlap between idiopathic pulmonary fibrosis and COVID-19
Authors: Richard J. Allen, Beatriz Guillen-Guio, Emma Croot, Luke M. Kraven, Samuel Moss, Iain Stewart, R. Gisli Jenkins, Louise V. Wain
Journal: European Respiratory Journal (2022)

<b>Positive genetic correlations for COVID-19 and IPF point to interferon-mediated innate immunity in both response to infection and chronic disease whilst negatively correlated signals highlight implications for drug targeting</b>https://bit.ly/37MMxZa
Re: Øyvind Ulvik, Mathias Sørstrand Æsøy, Patrick Juliebø-Jones, Peder Gjengstø, Christian Beisland. Thulium Fibre Laser versus Holmium:YAG for Ureteroscopic Lithotripsy: Outcomes from a Prospective Randomised Clinical Trial. Eur Urol. 2022;82:73–9
Authors: Hyung Joon Kim, Khurshid R. Ghani
Journal: European Urology (2022)
Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy
Authors: Yubi Lin, Ruonan Liu, Yanling Huang, Zhe Yang, Jianzhong Xian, Jingmin Huang, Zirui Qiu, Xiufang Lin, Mengzhen Zhang, Hui Chen, Huadong Wang, Jiana Huang, Geyang Xu
Journal: Acta Pharmaceutica Sinica B (2022)

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2−/−). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2−/− mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2−/− mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR–4EBP1–PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.
The “Cold Revolution” – cold snare resection of sessile colorectal polyps
Authors: Stefan Seewald, Tiing Leong Ang
Journal: Endoscopy (2022)

In recent years, the use of cold snare polypectomy (CSP) for sessile colorectal polyps less than 10 mm in size has gained widespread popularity. Dedicated cold snares that facilitate endoscopic resection are now widely available. CSP is easy and quick to perform with no need for submucosal injection. CSP avoids potential complications related to the use of electrocautery. Unlike thick-stalked pedunculated polyps and large sessile polyps, which are supplied by larger blood vessels, small non-pedunculated or flat lesions less than 10 mm in size are not supplied by such vessels, so the need to use electrocoagulation to prevent immediate severe bleeding after endoscopic resection is less of a concern. The European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline suggests the use of CSP for sessile polyps of 6–9 mm in size because of its safety profile [1]. The time interval for surveillance colonoscopy is based on the assumption that complete endoscopic resection of the detected adenomas will have been achieved. Incomplete resection of colorectal adenomas is an important cause of post-colonoscopy colorectal cancer [2]. There is uncertainty about the relative efficacy of CSP compared with hot snare polypectomy (HSP), and also about the generalizability of the currently published outcome data to more diverse patient populations and endoscopy practice settings [3].